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HK1171370A1 - A method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition - Google Patents

A method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition Download PDF

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Publication number
HK1171370A1
HK1171370A1 HK12112125.9A HK12112125A HK1171370A1 HK 1171370 A1 HK1171370 A1 HK 1171370A1 HK 12112125 A HK12112125 A HK 12112125A HK 1171370 A1 HK1171370 A1 HK 1171370A1
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Hong Kong
Prior art keywords
disorder
metadoxine
cognitive
group
use according
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HK12112125.9A
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Chinese (zh)
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HK1171370B (en
Inventor
里娜．雅明
達利亞．馬吉多
达利亚．马吉多
亞龍．伊蘭
亚龙．伊兰
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阿尔考布拉有限公司
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Publication of HK1171370B publication Critical patent/HK1171370B/en

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    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract

The present invention provides uses of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted, for the preparation of a medicament for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition in a subject. Additionally, the invention provides use of said salt adducts for the preparation of medicaments for the improvement of cognitive functions in a healthy subject.

Description

Methods for treating, alleviating symptoms of, relieving, ameliorating, and preventing cognitive diseases, disorders, or conditions
Technical Field
The present invention relates to methods of treating and/or ameliorating and/or improving and/or preventing a cognitive disease, disorder or condition in a subject in need thereof using metadoxine and derivatives thereof or compositions comprising the same.
Background
Changes in cognitive function may result in changes in cognitive status or changes in cognitive function and may manifest as memory impairment (memory impairment) or learning disability (learning disability) or any type of functional change.
Attention Deficit Hyperactivity Disorder (ADHD) is characterized by generalized and damaging symptoms of inattention, hyperactivity, and impulsivity. ADHD/ADD is one of the most thoroughly studied diseases in medicine. It is associated with a wide range of adverse outcomes for the affected subjects and a significant financial burden on the home and society, making it a significant public health problem.
Amnesia (amnesia) is a disorder that can be defined by memory deficits (loss of memory) due to some agitated or dready psychological experience, brain damage or a cascade of emotional events. Amnesia has different causes and causes, such as organic and functional. Organic amnesia is caused by brain damage caused by external factors, which may be due to physical shock (e.g., trauma or disease). Functional amnesia is caused by psychological factors. There are many reasons why amnesia-like phenomena can be caused: head injury, severe disease, high fever, seizure (seizure), emotional shock or hysteria (hysteria), alcohol-related brain injury (alcoholic-related brain damage), drugs, stroke, Alzheimer's disease and brain surgery, any type of metabolic disease (e.g. liver or uremic encephalopathy), any disease that alters blood flow in the brain or alters neurotransmission in the brain or is a result of an increase or decrease in any type of metabolite in the brain, diseases associated with amyloid accumulation in the brain or with altered electrical or metabolic function or any type of mechanistic change in the brain.
Fatigue is associated with most lifestyle and mental health conditions, and is described in the literature as a complex phenomenon representing a reduced ability to perform or complete mental or physical tasks or a reduced response after continuous activity, and a reduced motivation to perform tasks. The level of fatigue experienced by an individual relates to the cumulative past pattern of daily activity and the period of sleep and activity. In summary, fatigue is caused by time spent on tasks, natural day and night factors, and inadequate sleep. Alertness (alert), on the other hand, is a state of readiness and attention that is achieved without artificial or natural enhancement.
Concentration difficulties are symptoms that can arise from physical and psychological or emotional problems. The symptoms of lack of concentration or deficit may or may not be associated with other memory-related symptoms (e.g., amnesia). Physical medical conditions that affect attention include Lyme disease, whiplash (whiplash), and a variety of other conditions. Psychological conditions that can impair attention concentration include depression, certain anxiety disorders, and stress. Sleep disorders (e.g., insomnia or sleep apnea) can also impair attention-concentration.
Metadoxine (metadoxine) is a pyridoxine-pyrrolidone carboxylate (also known as pyridoxine (pyridoxol) L, 2-pyrrolidone-5 carboxylate or pyridoxine (pyridoxine) 5-oxo-2-pyrrolidone-carboxylate) that has significant alcohol scavenging properties. Metadoxine has been used in the treatment of acute alcohol intoxication (intoxication), intoxication (poisening) and certain other acute alcohol syndromes (reviewed in adolorato et al, int.j. immunopathol. pharmacol. (2003) 16: 207-. Long-term data show that metadoxine is safe for use in humans.
Metadoxine accelerates alcohol clearance from blood and tissues, helps restore the functional structure of the liver, and alleviates neuro-psychological disorders and related syndromes associated with chronic alcoholism. In animal studies, metadoxine increases plasma clearance and urinary excretion of ethanol, inhibits increased fatty acid ester production in the liver during chronic alcohol intake, reduces oxidative stress, and prevents glutathione depletion in liver tissues (Antonelli et al, Pharmacol. Res. Commun. (1984) 16: 189-. In the brain, metadoxine increased GABA and acetylcholine levels in the frontal parietal cortex of guinea pigs.
Metadoxine is an ion pair between Pyrrolidone Carboxylate (PCA) and pyridoxine (vitamin B6), which are linked in a single product by salt formation. Pairing with PCA synergistically increases the pharmacological activity of pyridoxine (see, e.g., U.S. patent No. 4,313,952). Metadoxine is readily soluble in water and gastric juices. The medicine has the advantages of rapid oral absorption and high bioavailability (60-80%). Metadoxine has a short half-life in human serum (40-60 minutes) with no significant difference between oral and intravenous administration (Addoloro et al, supra; Lu Yuan et al, Chin. Med. J.2007120(2) 160-.
Metadoxine is marketed in various countries as a prescription drug in the form of 500mg tablets and 300mg injections. Tablets contained 500mg metadoxine, microcrystalline cellulose and magnesium stearate. The ampoule contains 300mg metadoxine, sodium metabisulfite, sodium EDTA, methylparaben and water.
US 6,541,043 describes compositions and methods for treating attention deficit/Hyperactivity Disorder (ADHD), comprising Dimethylaminoethanol (DMAE) in combination with various agents, particularly vitamin B6, and optionally conventional medications for treating ADHD. WO03/003981 discloses compositions for structural/functional nutritional support for subjects with poor concentration (focus), concentration and/or memory and subjects subjectively experiencing transient mental fatigue or poor cognitive function. These compositions contain, inter alia, the B vitamins, including B6 and L-pyroglutamic acid, as well as many other ingredients. WO09/004629 describes a method for reducing or preventing symptoms or effects of alcohol intake comprising administering metadoxine. US20070248696 describes a composition for improving neuromuscular facilitation (also known as "muscle memory") and enhancing cognitive function (e.g. memory and attention-concentration) in the form of a dietary supplement comprising vitamin B6 and many other ingredients. US20090081179 discloses polyunsaturated fatty acids and e.g. vitamin B6 and other uses in the treatment of Parkinson's disease, Huntington's chorea, epilepsy, schizophrenia, paranoia, depression, sleep disorders, impaired memory function, neurological diseases, dementia and ADHD. EP 511943 describes pyroglutamic acid derivatives as enhancers of learning processes and memory. The effect of administration of metadoxine on memory recovery was tested against withdrawal from chronic alcoholism. Vitamin B6 was administered to a control group of similar patients. As a result, metadoxine was found to help restore short-term memory after 1-2 months of withdrawal, and its effect was superior to vitamin B6[ Sinforiani et al, clin. 103-111(1990)]. WO2010/013242 discloses salt adducts comprising at least one positively charged group being a pyridoxine or a derivative thereof and at least one carboxylated 5-to 7-membered lactam ring, which are also optionally substituted, methods for their preparation, and pharmaceutical compositions and medicaments comprising them for the treatment of diseases or disorders related to or caused by alcohol intake.
There is a need for methods that can treat, alleviate symptoms, alleviate, ameliorate, and prevent cognitive diseases, disorders or conditions, cognitive behaviors and functions, and sustain these improvements persistently.
It is an object of the present invention to provide methods for treating these cognitive disorders and deficits using metadoxine and its derivatives or compositions comprising them. It is another object of the present invention to provide a composition comprising metadoxine or a derivative thereof for the long-term treatment of cognitive deficits. These and other objects of the invention will become apparent as the description proceeds.
Disclosure of Invention
The present invention is intended to solve one or more of the above-mentioned problems by providing various methods for improving cognitive performance by administering a composition comprising metadoxine or a derivative thereof to a subject in need thereof. Also provided are compositions of metadoxine and/or metadoxine derivatives formulated for sustained or controlled release, optionally further comprising an immediate release component or metadoxine derivatives, and methods of using these sustained or controlled release or combined metadoxine or metadoxine derivative formulations of the invention. The composition may comprise metadoxine or a metadoxine derivative formulated for sustained or controlled release. In some aspects, the composition comprising metadoxine or a metadoxine derivative can have a portion of metadoxine or a metadoxine derivative formulated for sustained or controlled release and a portion of metadoxine or a metadoxine derivative formulated for immediate release.
In one of its aspects, the present invention provides a method of treating, alleviating a symptom, alleviating, ameliorating, and preventing a cognitive disease, condition, or disorder in a healthy subject or a patient in need thereof, the method comprising administering to the subject an effective amount of metadoxine or a derivative thereof.
In another aspect, the present invention provides a method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition in a subject, said method comprising administering to said subject an effective amount of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5-to 7-membered lactam ring, optionally additionally substituted.
In a further aspect, the present invention provides a method for improving cognitive function in a healthy subject, the method comprising administering to the subject an effective amount of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5-to 7-membered lactam ring, optionally additionally substituted.
When referring to "metadoxine", it should be understood to encompass the salt adduct pyridoxine L-2-pyrrolidone-5-carboxylate. Metadoxine is a salt of the corresponding anion of L-2-pyrrolidone-5-carboxylic acid (L-2-pyroglutamic acid) (1) and the protonated derivative of pyridoxine (vitamin B6) (2) having the following structure:
when referring to a "metadoxine derivative", it is to be understood as encompassing any other salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5-to 7-membered lactam ring, optionally additionally substituted.
In all embodiments of the invention, the positively charged moiety is a compound of formula (I):
wherein R is1Is straight or branched C1-C6An alkyl group; r2Selected from-OH, straight or branched C1-C6Alkoxy and straight or branched C1-C6An alkoxycarbonyl group; r3And R4Each independently selected from: formyl, optionally with at least one halogen, amine, hydroxy, C1-C6Alkoxy, mercapto and C1-C6Alkoxycarbonyl-substituted straight or branched C1-C6An alkyl group.
In another embodiment of the invention, the carboxylated lactam ring is selected from the group consisting of:
wherein R is6Selected from H, linear or branched C optionally substituted with at least one halogen1-C6Alkyl, straight or branched C2-C6Alkenyl, straight-chain or branched C2-C6Alkynyl, cycloalkyl, aryl and heteroaryl, optionally with C1-C6Alkyl substitution; r7、R8、R9、R10、R11、R12、R13And R14Each independently selected from H, straight or branched C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, cycloalkyl, aryl and heteroaryl, optionally substituted with at least one group selected from: c1-C6Alkyl, halogen, amino, cyano, nitro, mercapto, C1-C6Alkoxy, aminocarbonyl, C1-C6Alkoxycarbonyl group, C1-C6Carboxyalkyl, C1-C6Alkoxycarbonylalkyl and amidino.
In yet another embodiment of the present invention, the salt adduct is selected from the following:
when referring to a cognitive disease, disorder or condition that is alleviated, ameliorated, improved or prevented by the methods of the invention, it should be understood to encompass at least one of the following non-limiting conditions: attention deficit/hyperactivity disorder (ADHD), memory disorder (amnesia), arousal disorder (inpatient wakefulness), mental fatigue disorders (including disease-related fatigue), shift work sleep disorder, narcolepsy (narcolepsy), Obstructive sleep apnea/Hypopnea Syndrome (obstractive sleep/Hypopnea Syndrome), depression, Substance dependence (Substance) including, for example, addictive substances, parkinson's disease, schizophrenia, poor concentration (porous concentration), and poor concentration (porous focus), or any combination thereof.
In another aspect, the invention provides a method for treating, alleviating the symptoms, reducing, ameliorating and preventing a neurobehavioral disorder (e.g., ADHD and/or ADD) in a patient or healthy subject in need thereof experiencing symptoms associated with or linked to a persistent or transient neurobehavioral disorder (e.g., ADHD and/or ADD), said method comprising administering to said subject an effective amount of metadoxine or a derivative thereof.
When referring to a neurobehavioral disorder that is alleviated, ameliorated, or prevented by a method of the invention, it should be understood to encompass at least one of the following non-limiting conditions: attention Deficit Disorder (ADD), Attention Deficit Hyperactivity Disorder (ADHD), poor concentration, or any combination or symptom thereof.
The methods of the invention may also improve the wakefulness of a subject (of any age, e.g., a child, adolescent or adult subject) who experiences excessive sleep due to one of the following non-limiting diagnosed sleep disorders: obstructive sleep apnea/hypopnea, shift work sleep disorder, and narcolepsy.
In addition, the cognitive diseases, disorders or conditions that are alleviated, ameliorated, improved or prevented by the methods of the invention can also include any condition associated with no learning ability, memory impairment, cognitive dysfunction, changes in cognitive function (including alzheimer's disease) or any type of encephalopathy (including uremic encephalopathy and hepatic encephalopathy).
In addition, a neurobehavioral disorder that is alleviated, improved, or prevented by a method of the invention can also include any condition associated with any symptom associated with or associated with a neurobehavioral disorder (e.g., learning deficit, memory impairment, cognitive dysfunction, change in cognitive function, etc.).
Thus, in any of the various embodiments of the methods of the invention described hereinabove, the composition may comprise metadoxine or a metadoxine derivative formulated for immediate release, sustained release, controlled release, or a combination of any of the foregoing.
When referring to cognitive function, it should be understood to encompass at least one of the following non-limiting list: temporary or long term no learning ability, temporary or long term memory impairment, temporary or long term cognitive dysfunction, temporary or long term cognitive function change, temporary or long term attention concentration impairment, temporary or long term attention convergence impairment, temporary or long term arousal impairment, temporary or long term mental fatigue disorder, temporary or long term shift work sleep impairment, or any combination thereof.
It will be understood that when reference is made to improvement of cognitive function in a healthy subject, it is intended to include any change (slight or significant) in the subject's cognitive status. In particular, the improvement may be significant in at least one of the following non-limiting list of disorders: temporary or long term no learning ability, temporary or long term memory impairment, temporary or long term cognitive dysfunction, temporary or long term cognitive function change, temporary or long term attention concentration impairment, temporary or long term attention convergence impairment, temporary or long term arousal impairment, temporary or long term mental fatigue condition, temporary or long term shift work sleep impairment, or any combination thereof.
In certain other aspects, the invention provides methods for increasing the mean t of metadoxine or a metadoxine derivative in the blood of a subjectmaxThe method of (a), comprising administering a metadoxine or metadoxine derivative composition of the invention formulated for sustained or controlled release, optionally comprising a portion of metadoxine or metadoxine derivative formulated for immediate release.
In certain aspects, the invention provides the use of any one of the compositions of the invention for the manufacture of a therapeutic and/or pharmaceutical composition and/or medicament for carrying out each of the methods of the invention described herein, e.g., for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition in a healthy patient or a patient suffering from attention deficit/hyperactivity disorder (ADHD/ADD), memory disorders (amnesia), mental fatigue conditions, poor concentration and poor concentration. The subject may be a child, adolescent, adult or elderly.
The invention also relates to any condition associated with an inability to learn, memory impairment, any change in cognitive function (including alzheimer's disease) associated with a change in blood flow, sclerosis, amyloid deposition, a change in neurotransmitters in the brain, a change in metabolism (e.g. ammonia accumulation), any type of brain disease (including uremic and hepatic encephalopathy) or any type of functional change caused by a change in the level of any substance.
Changes in cognitive function can result in changes in cognitive status, or in changes in cognitive function, and can be manifested in memory impairment or lack of learning ability or any type of functional change.
In any of the various embodiments of the compositions of metadoxine or metadoxine derivatives described herein (e.g., metadoxine or metadoxine derivatives formulated for immediate release, sustained release, controlled release, or a combination of any of the foregoing), metadoxine can consist of or comprise a pharmacologically compatible metadoxine derivative.
The present invention will be described in more detail with reference to the accompanying drawings.
Drawings
In order to understand the invention and to see how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:
figure 1 shows the release rate of certain metadoxine compositions of the invention described in example 1. The figure illustrates the difference between immediate and slow release formulations of metadoxine. Metadoxine (%) release versus time (hours).
Figure 2 shows the release rate of an immediate release formulation compared to the release from a slow release tablet.
Detailed Description
In a first aspect of the present invention there is provided a method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition in a subject, said method comprising administering to said subject an effective amount of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5-to 7-membered lactam ring, optionally additionally substituted.
In another aspect of the present invention there is provided a method for improving cognitive function in a healthy subject, said method comprising administering to said subject an effective amount of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5-to 7-membered lactam ring, optionally additionally substituted.
In another aspect of the present invention there is provided the use of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5-to 7-membered lactam ring, optionally additionally substituted, for the preparation of a medicament for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition in a subject.
In a further aspect of the present invention there is provided the use of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5-to 7-membered lactam ring, optionally additionally substituted, for the preparation of a medicament for improving cognitive function in a healthy subject.
In all embodiments of the invention, the positively charged moiety is a compound of formula (I):
wherein R is1Is straight or branched C1-C6An alkyl group; r2Selected from-OH, straight or branched C1-C6Alkoxy and straight or branched C1-C6An alkoxycarbonyl group; r3And R4Each independently selected from formyl, optionally with at least one halogen, amine, hydroxy, C1-C6Alkoxy, mercapto and C1-C6Alkoxycarbonyl-substituted straight or branched C1-C6An alkyl group.
In other embodiments of the present invention, the carboxylated lactam ring is selected from the group consisting of:
wherein R is6Selected from H, linear or branched C optionally substituted with at least one halogen1-C6Alkyl, straight or branched C2-C6Alkenyl, straight-chain or branched C2-C6Alkynyl, cycloalkyl, aryl and heteroaryl, optionally with C1-C6Alkyl substitution; r7、R8、R9、R10、R11、R12、R13And R14Each independently selected from H, straight or branched C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, cycloalkyl, aryl, and heteroaryl, optionally substituted with at least one group selected from: c1-C6Alkyl, halogen, amino, cyano, nitro, mercapto, C1-C6Alkoxy, aminocarbonyl, C1-C6Alkoxycarbonyl group, C1-C6Carboxyalkyl, C1-C6Alkoxycarbonylalkyl and amidino.
In other embodiments of the present invention, the carboxylated lactam ring is a compound of formula (II):
the positively charged moiety is compound (2):
wherein R is6、R7、R8、R9And R10As defined above.
In other embodiments, the carboxylated lactam ring is compound (1):
the positively charged moiety is a compound of formula (I):
wherein R is1、R2、R3And R4As defined above.
In other embodiments, R1Is C1-C6Alkyl radical, and R2、R3And R4As defined above.
In other embodiments, R2Is selected from-OH and C1-C6An alkoxy group; and R is1、R3And R4As defined above.
In other embodiments, R3is-CH2R15Wherein R is15Is selected from-C1-C6Alkoxy, -OH and-NH3 +(ii) a And R is1、R2And R4As defined above.
In other embodiments, R4Selected from formyl and-CH2R16Wherein R is16Is selected from-C1-C6Alkoxy and-OH; and R is1、R2And R3As defined above.
In other embodiments, R1is-CH3，R2is-OH, R3And R4Are all-CH2OH。
In other embodiments, the carboxylated lactam ring is a compound of formula (II):
wherein R is6、R7、R8、R9And R10As defined above. In some embodiments, R6Is C1-C6An alkyl group. In other embodiments, R9Is C1-C6An alkyl group.
In other embodiments, the carboxylated lactam ring is a compound of formula (III):
the positively charged moiety is a compound of formula (I):
wherein R is1、R2、R3、R4、R6、R7、R8、R9、R10、R11And R12As defined above.
In other embodiments, the carboxylated lactam ring is a compound of formula (IV):
the positively charged moiety is a compound of formula (I):
wherein R is1、R2、R3、R4Wherein R is6、R7、R8、R9、R10、R11、R12、R13And R14As defined above.
In still other embodiments, the positively charged moiety is compound (2):
in some embodiments of the invention, the salt adduct is selected from the following:
in other embodiments, the cognitive disease, disorder or condition is selected from the group consisting of: attention deficit/hyperactivity disorder (ADHD/ADD), memory disorder (amnesia), arousal disorder, mental fatigue disorder, shift work sleep disorder, narcolepsy, obstructive sleep apnea/hypopnea syndrome, poor concentration of attention (or concentration) and poor concentration of attention (or focus), or any combination thereof.
In still other embodiments, the cognitive disease, disorder or condition is selected from the group consisting of: learning disability, memory impairment, cognitive dysfunction, cognitive function alterations (including alzheimer's disease) or any type of encephalopathy (including uremic encephalopathy and hepatic encephalopathy).
In yet other embodiments, the cognitive disease, disorder or condition is a neurobehavioral disease, disorder or condition.
In still other embodiments, the neurobehavioral disease, disorder or condition is selected from: attention Deficit Hyperactivity Disorder (ADHD), Attention Deficit Disorder (ADD), memory disorders, poor concentration, and poor concentration.
In still other embodiments, the cognitive disease, disorder or condition is selected from the group consisting of: attention Deficit Disorder (ADD) or hyperactivity disorder (ADHD/ADD), memory disorder (amnesia), arousal disorder, mental fatigue disorder, shift work sleep disorder, narcolepsy, obstructive sleep apnea/hypopnea syndrome, poor concentration and poor concentration, or any combination thereof.
In other embodiments, the cognitive function is selected from the group consisting of: temporary or long term no learning ability, temporary or long term memory impairment, temporary or long term cognitive dysfunction, temporary or long term cognitive function change, temporary or long term attention concentration impairment, temporary or long term attention convergence impairment, temporary or long term arousal impairment, temporary or long term mental fatigue disorder, temporary or long term shift work sleep impairment, or any combination thereof.
In still other embodiments, the subject is a child, adolescent, adult, or elderly.
In all embodiments of the invention, the salt adduct is formulated as a sustained release, delayed release or controlled release dosage form.
In other embodiments of the present invention, the salt adduct is formulated as a sustained release, delayed release or controlled release dosage form in combination with a salt adduct formulated as an immediate or burst effect (burst effect) dosage form.
In other embodiments of the invention, the salt adduct is formulated to deliver up to 0.1-1000mg/kg body weight/day of the salt adduct, preferably 1-400mg/kg body weight of the salt adduct in a single dose administration or portion thereof. In still other embodiments, the salt adduct is formulated to deliver up to 100-700mg/kg body weight/day of the salt adduct.
In other embodiments of the present invention, the salt adduct is formulated with at least one other pharmaceutically active agent.
In further aspects of the invention there is provided a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5-to 7-membered lactam ring, optionally additionally substituted, for use in the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition in a subject.
In another aspect, the present invention provides a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5-to 7-membered lactam ring, optionally additionally substituted, for use in improving cognitive function in a healthy subject.
Definition of
For convenience, certain terms used in the specification, examples and appended embodiments are summarized herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
An indefinite term "a" or "an" as used herein refers to one or more than one (i.e., at least one). For example, "an element" means one element or a plurality of elements.
The term "including" as used herein means, and is used interchangeably with, the phrase "including but not limited to".
The term "or" as used herein means, and is used interchangeably with, the word "and/or," unless the context clearly dictates otherwise.
The term "such as" as used herein refers to and is used interchangeably with the phrase "such as, but not limited to".
The term "prophylactic" or "therapeutic" treatment refers to the administration of one or more compositions of the present invention to a subject. If administered prior to clinical manifestation of the unwanted condition (e.g., clinical or other unwanted state of the host animal), the treatment is prophylactic, i.e., it contributes to preventing the occurrence of the unwanted condition (i.e., protecting the subject from the occurrence of the unwanted condition), whereas if administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to reduce, ameliorate or prevent progression of the unwanted condition or side effects produced thereby).
The term "therapeutic effect" refers to a local or systemic effect in an animal (especially a mammal, and more especially a human) caused by a pharmacologically active substance. Thus, the term means any substance intended for use in diagnosing, curing, alleviating, treating or preventing disease or for enhancing a desired physical or mental development and condition in an animal or human. The term "therapeutically effective amount" means that amount of the substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment. In certain embodiments, a therapeutically effective amount of a compound or composition depends on its therapeutic index, solubility, and the like. For example, certain metadoxine or metadoxine derivative formulations of the invention can be administered in an amount sufficient to produce a reasonable benefit/risk ratio appropriate for the selected treatment, which can be determined by one skilled in the art.
The term "effective amount" refers to an amount of a therapeutic agent that produces at least one desired result when administered to a subject in an appropriate dosage and regimen.
A "subject" or "patient" to be treated by the methods of the invention may mean a human or non-human animal (preferably a mammal). The term "subject" as used herein may refer to a healthy individual or a subject suffering from any cognitive problem. The terms "subject" and "healthy subject" and "subject in need" and "patient in need" as used herein do not include subjects affected by alcohol after any form of alcohol consumption, alcoholics (alcohol addicts) and abstinence alcoholics.
The terms "cognition" or "cognitive function" or "cognitive problem" or "cognitive disorder" or "cognitive malfunction" or "cognitive disease, disorder or condition" and the like are used interchangeably herein, and may be used herein to refer to any cognitive function including, but not limited to, attention deficit/hyperactivity disorder (ADHD/ADD), memory disorders (amnesia), mental fatigue disorders (including disease-related fatigue), poor concentration and poor concentration, and any disorder associated with a lack of learning ability, memory impairment, any change in cognitive function associated with blood flow, sclerosis, amyloid deposition, changes in neurotransmitters in the brain, changes in metabolism (e.g. ammonia accumulation) (including alzheimer's disease), any type of encephalopathy (including uremic encephalopathy and perceptual encephalopathy), or any type of functional change due to any change in substance levels.
In this connection, cognitive dysfunctions which may be mentioned include in particular any disorder resulting from: changes in blood flow to the whole or part of the brain, such as stroke; acid-base equilibrium is changed; electrolyte change; any metabolite level change (increase or decrease) (e.g., uric acid or ammonia); deposition of any matrix (e.g., amyloid) in any part of the brain, such as in alzheimer's disease or parkinson's disease; changes affecting any part of the immune system of the brain (whether peripheral or central), such as multiple sclerosis or different types of lupus erythematosus; an alteration in the level or function of any cytokine or chemokine; the action of drugs that target or target the brain or affect the brain in an indirect manner; an alteration in a neurotransmitter; and any change in nerves or synapses in the brain.
The terms "neurobehavioral" or "neurobehavioral functions" or "neurobehavioral problems" or "neurobehavioral disorders" or "neurobehavioral dysfunctions" and the like are used interchangeably herein and may be used herein to refer to any cognitive function including, but not limited to, attention deficit/hyperactivity disorder (ADHD/ADD), memory disorders (amnesia), poor concentration and poor concentration, as well as any condition associated with or associated with an inability to learn, memory disorders, such as poor performance in social (family, community, etc.), educational (class, stadium, etc.) environments.
The present invention relates to any known ADHD type:
(i) main multi-action-impulse: in this regard, although inattention may still be present to some extent, most symptoms belong to the category of hyperactivity impulses, and there are some inattention symptoms,
(ii) the main attention is not focused: although hyperactivity-impulsion may still be present to some extent, most symptoms fall into the inattentive category and fewer hyperactivity-impulsion symptoms are present; children with this subtype are less likely to want to meet or have difficulty meeting other children. They may sit quietly, but they do not notice what they are doing. Thus, these children may be overlooked and parents and teachers may not notice the symptoms of ADHD.
(iii) Combined hyperactivity-impulsion and inattention: there are some symptoms of inattention and some of the hyperactivity-impulsivity.
The inattentive type of symptoms may include:
● objects may easily become distracted, miss details, forget, and frequently transition from one activity to another
● it is difficult for the subject to concentrate attention on a thing
● unless it is pleasurable, the object may become bored with the task after only a few minutes
● objects may have difficulty concentrating on organizing and completing tasks or learning new things
● objects may be difficult to accomplish or hand over to homework, often losing the goal needed to accomplish the task or activity (e.g., pencil, toy, job)
● when speaking to it, the subject does not seem to be listening
● objects may be daytime dreams, become confusing, and move slowly
● objects may have difficulty processing information as quickly and accurately as others
● objects may resist compliance indications.
The major hyperactive-impulsive type symptoms include:
● the subject can sit on or be restless and twist on his seat
● the subject can speak continuously
● the object can bump, touch or play with anything or everything it sees
● it may be difficult for a subject to sit quietly during eating, school, and storytelling
● the object may be constantly moving around
● subjects may have difficulty engaging in quiet tasks or activities.
Other manifestations of predominantly impulsive motion may include:
● the subject may be very impatient
● the subject may be out of the way and out of the way to make inappropriate utterances, represent their emotions unconstrained, and act without regard to consequences
● objects may have difficulty waiting for something they want or waiting for their sequence in a game
The term "salt adduct" as used herein is intended to encompass the salt product of the direct addition of two or more different ions, wherein the total charge of the salt adduct is zero. In certain embodiments, the salt adduct comprises one positively charged moiety having a single positively charged functional group (i.e., the positively charged moiety carries a net charge of + 1) and one negatively charged moiety having a single negatively charged functional group (i.e., the negatively charged moiety carries a net charge of-1). In certain embodiments, the salt adduct comprises one positively charged moiety having two identical or different positively charged functional groups (i.e., the positively charged moiety carries a net charge of + 2) and two identical or different negatively charged moieties, and each has a single negatively charged functional group (i.e., each of the negatively charged moieties carries a net charge of-1). In certain embodiments, the salt adduct comprises two identical or different positively charged moieties, each having one positively charged functional group (i.e., each positively charged moiety carries a net charge of + 1), and one negatively charged moiety having two identical or different negatively charged functional groups (i.e., the negatively charged moiety carries a net charge of-2). In certain embodiments, the salt adduct comprises a positively charged moiety (from one or more same or different positively charged functional groups) with a net charge of + n and a negatively charged moiety (from one or more same or different negatively charged functional groups) with a net charge of-n, where n is an integer that can equal 1, 2, 3, 4, 5, or 6.
As used herein, the "positively charged moiety of a salt adduct" of the invention is the corresponding acid of pyridoxine or any derivative thereof. In certain embodiments, the charge is positively chargedThe positive charge of the moiety is derived from the pyridoxine protonated basic nitrogen atom (e.g., in compound (2)) or any derivative thereof (e.g., a compound of formula (I)). In certain embodiments, a positively charged functional group (e.g., -NH)3 +、-CH2NH3 +、-NH2R+、-NHR2 +Wherein each R is independently C1-C6Alkyl) substituted for the positively charged pyridoxine derivative, which may, in some embodiments, be present in addition to the positively charged protonated basic nitrogen atom in the pyridine ring.
As used herein, the "carboxylated 5-to 7-membered lactam ring" of the salt adduct of the invention is intended to encompass the use of negatively charged carboxylate groups (-COO)-) A substituted gamma-lactam, delta-lactam or epsilon-lactam ring. In certain embodiments, the carboxylate groups are substituted on the carbon atom of the lactam ring adjacent to the amide nitrogen. In another embodiment, the carboxylated lactam ring is L-2-pyrrolidone-5-carboxylic acid salt (compound (1)). In other embodiments, the carboxylate groups are substituted at any position of the lactam ring. In certain embodiments, the carboxylated 5-to 7-membered lactam ring may be substituted with other substituents at any position on the lactam ring. The term "halogen" as used herein means F, Cl, Br or I.
The term "C" as used herein1-C6Alkyl "denotes a saturated, branched or straight-chain hydrocarbon having 1, 2, 3, 4, 5 or 6 carbon atoms. General formula C1-6Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
The term "C" as used herein2-C6Alkenyl "denotes a branched or straight chain hydrocarbon having 2, 3, 4, 5 or 6 carbon atoms and having at least one double bond between any two carbons of the chain. Examples of such groups include, but are not limited to: vinyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 1, 3-butadienyl group, 1-butadienyl groupAlkenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, and the like.
The term "C" as used herein2-C6Alkynyl "represents a branched or straight chain hydrocarbon having 2, 3, 4, 5 or 6 carbon atoms and having at least one triple bond between any two carbon atoms of the chain. Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, and the like.
The term "C" as used herein1-C6Alkoxy "means-O-C1-6Alkyl radical, wherein C1-C6Alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy and the like.
The term "C" as used herein1-C6Alkylthio "means-S-C1-6Alkyl radical, wherein C1-6Alkyl is as defined above. Representative examples are methylthio, ethylthio, isopropylthio, n-propylthio, butylthio, pentylthio and the like.
The term "cycloalkyl" as used herein denotes a monocyclic carbocyclic group having 3, 4, 5, 6, 7 or 8 carbon atoms, but may also contain heteroatoms (e.g., N, O and/or S). Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The term "aryl" as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalene, azulene and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic ring systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1, 2, 3, 4-tetrahydronaphthyl, 1, 4-dihydronaphthyl, and the like.
The term "heteroaryl" as used herein refers to a substituted or unsubstituted ring system wherein at least one ring is an aromatic ring in which at least one atom is a non-carbon atom, wherein the non-carbon atom may be, for example, a nitrogen, sulfur or oxygen atom.
The term "C" as used herein1-C6Alkoxycarbonyl means-C (O) O-C1-6Alkyl radical, wherein C1-6Alkyl is as defined above.
The term "C" as used herein1-C6Alkoxy "and" C1-C6Alkylthio "is independently C1-6-O-and C1-6-S-, wherein C1-6Alkyl is as defined above.
The term "hydroxy" as used herein refers to an-OH group. The term "mercapto" as used herein refers to the-SH group. The term "formyl" as used herein refers to a COH group. The term "cyano" as used herein refers to the group-CN. The term "nitro" as used herein means-NO2A group.
The term "amine" as used herein means-NH3Or any primary amine (-NH)2R), secondary amine (-NHR)2) Tertiary amines (-NR)3) Or quaternary amines (-NR)4 +) Wherein each R may be the same or different and is independently selected from H, C defined hereinabove1-C6Alkyl radical, C1-C6Alkenyl radical, C1-C6Alkynyl.
The term "C" as used herein1-C6Carboxyalkyl "means the radical-CO- (C)1-C6Alkyl) in which C1-6Alkyl is as defined above.
The term "aminocarbonyl" as used herein means-CONR2Wherein each group R is independently selected from H, C defined hereinbefore1-C6Alkyl radical, C1-C6Alkenyl radical, C1-C6Alkynyl.
The term "alkoxycarbonylalkyl" as used herein means-OCO- (C)1-C6Alkyl) radical, in which C1-6Alkyl is as defined above.
The term "amidino" as used herein means-C (═ NH) -NH2A group.
The term "optionally substituted" as used herein means that the moiety referred to is unsubstituted or substituted with one or more specified substituents. When a designated moiety is substituted with more than one substituent, the substituents may be the same or different.
The substituent may include, for example, a halogen, a hydroxyl group, a carbonyl group (e.g., a carboxyl group, an alkoxycarbonyl group, a formyl group, or an acyl group), a thiocarbonyl group (e.g., a thioester group, a thioacetate group, or a thiocarbamate group), an alkoxy group, an alkylthio group, an acyloxy group, a phosphoryl group, a phosphate group, a phosphonate group, an amino group, an imino group, an amidino group, an imino group, a cyano group, a nitro group, an azido group, a mercapto group (sulfydryl group), an alkylthio group, a sulfate group, a sulfonate group, a sulfamoyl group, a sulfonamide group, a sulfonyl group, a.
It is to be understood that the portions of the salt adducts of the present invention may each contain at least one chiral center and thus may exist or be separated in any of its stereoisomers, including enantiomers, diastereomers, or mixtures thereof (including but not limited to racemic mixtures). The present invention includes any possible stereoisomers (e.g., enantiomers, diastereomers), any mixtures thereof (including, but not limited to, racemic mixtures of any of the various moieties of the salt adducts of the present invention). Wherein the process described herein for preparing each part of the salt adducts of the present invention yields a mixture of stereoisomers, which can be separated by conventional techniques, such as preparative chromatography. The portions of the salt adducts of the present invention can each be prepared as their possible mixtures of stereoisomers, including but not limited to racemic mixtures thereof, or the individual stereoisomers (e.g., enantiomers, diastereomers) can be separated by chiral chromatography of the racemates. When referring to amino acids, it is to be understood that the present invention encompasses both natural and unnatural amino acids or any derivative thereof.
As used herein, the term "unnatural amino acid" refers to an amino acid having L and D configurations, or any derivative thereof, that is not listed as a structural component of a protein, while "natural amino acid" refers to an amino acid having L and D configurations, or any derivative thereof, that is a structural component of a protein.
Table 1 describes a number of examples of salt adducts of the present invention.
TABLE 1
Throughout this specification, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
The term "bioavailable" means that at least a portion of the amount of a particular compound is present in the systemic circulation. Formal calculations of oral bioavailability are described in terms of F values ("Fundamentals of clinical pharmacy," John G.Wegner, Drug Intelligent Publications issues; Hamilton, Ill.1975). F values are derived from the ratio of parent drug concentration in the systemic circulation (e.g., plasma) after intravenous administration to the parent drug concentration in the systemic circulation after non-intravenous (e.g., oral) administration. Thus, oral bioavailability within the scope of the present invention takes into account the ratio of the amount of parent drug detectable in plasma after oral administration compared to intravenous administration or the F-value.
The terms "treat," "treating," or "treatment" refer to the reduction, amelioration, alleviation, or at least alleviation of the symptoms of a condition, disease, or disorder, or the improvement of a defined metric associated with a condition, disease, or disorder, in a mammal (e.g., a human). Treatment as used herein also encompasses treatment of healthy individuals.
The term "acceptable derivative" with respect to metadoxine or a metadoxine derivative refers to any salt, conjugate, ester, complex, or other chemical derivative of metadoxine or any moiety comprising metadoxine that is capable of providing (directly or indirectly) metadoxine or a metabolite or functional residue thereof, or measurable metadoxine activity when administered to a subject. The term "physiologically compatible metadoxine derivative" is used interchangeably with the term "acceptable derivative" herein and refers to a functional, active, pharmaceutically acceptable metadoxine derivative.
The term "excipient" refers to an inactive substance that serves as a carrier for the active ingredient in the formulation.
The term "controlled release" refers to a formulation that delivers any drug at a controlled rate over a long period of time and is designed to achieve a desired drug level profile.
The term "sustained release" is used in its conventional sense to refer to a formulation that provides a long-term gradual release of the active substance, which in certain embodiments may also result in long-term substantially constant blood levels, i.e., controlled release.
The term "immediate release" is used in its conventional sense to refer to a formulation that provides non-delayed or controlled release of an active substance upon administration.
The term "half-life" of a substance is the time it takes for the substance to lose half of its pharmacological, physiological, or other activity. Biological half-life is an important pharmacokinetic parameter, usually denoted by the abbreviation t1/2。
The term "non-invasive" refers to a treatment modality that does not puncture the skin.
The term "non-chronic administration" is used herein interchangeably with the term "acute administration" and refers to the non-periodic administration of regular or irregular amounts or fractions of a drug to a subject. Non-chronic administration can be a single dose treatment or a multiple dose treatment, and can optionally be given over time. Typically (but not always) non-chronic administration is given to prevent non-chronic conditions. Certain chronic conditions may also benefit from non-chronic administration of the compositions of metadoxine or metadoxine derivatives described herein.
The term "chronic administration" refers to the regular administration of a regular amount of a drug to a subject. In some embodiments, the one or more chronic conditions, problems, or diseases are treated or prevented upon chronic administration. Chronic diseases are characterized by one or more of the following features: it is long-lasting, remains disabled, results from irreversible pathological changes, requires special training of the patient to recover, or is expected to require long-term supervision, observation, or care.
The term "single dose treatment" refers to the administration of a regular amount of a drug at a time. It is administered on an irregular basis to treat non-chronic conditions, depending on the individual's needs.
The term "tmax"refers to the time to peak concentration. The time to reach maximum concentration after single dose administration was calculated according to the formula:
wherein λ isαAnd λzApparent absorption and clearance rate constants, respectively.
Methods of treatment and prevention using compositions of metadoxine or metadoxine derivatives
In certain embodiments, the present invention provides methods for improving cognitive function and/or behavior in healthy patients or patients suffering from attention deficit hyperactivity disorder (ADHD/ADD), memory disorders (amnesia), mental fatigue disorders, poor attention concentration and poor attention convergence comprising administering a composition comprising metadoxine or a derivative thereof. In certain such embodiments, the method comprises non-chronically administering a composition comprising metadoxine or a derivative thereof.
In certain embodiments, the present invention provides methods for increasing the mean t of metadoxine or a metadoxine derivative in the blood of a subjectmaxTo improve or treat a cognitive disorder as defined herein, comprising administering a composition comprising metadoxine or a derivative thereof, and in particular wherein the composition comprises metadoxine or a derivative thereof formulated in whole or in part for sustained or controlled release. In certain such embodiments, the method comprises non-chronic administration of a composition comprising metadoxine or a derivative thereof, fully or partially formulated for sustained or controlled release. In certain embodiments of the invention, the mean t of metadoxine or metadoxine derivatives in the blood of the subjectmaxIncrease by 50%, 100%, 150%, 200%, 300%, 400%, 500% or more than 500%.
In certain embodiments, the present application provides methods for increasing the half-life (t) of metadoxine or a metadoxine derivative in the blood or serum of a subject1/2) To improve or treat a cognitive disorder described herein, comprising administering a composition comprising metadoxine or a derivative thereof, and in particular theretoThe compositions described in (1) comprise metadoxine or a derivative thereof, fully or partially formulated for sustained or controlled release, optionally comprising a portion of metadoxine or a metadoxine derivative formulated for immediate release. In certain embodiments of the invention, the metadoxine or the t of a metadoxine derivative is present in the blood or serum of the subject1/2Increase by 50%, 100%, 150%, 200%, 300%, 400%, 500% or more than 500%.
In certain of the above methods of the invention, metadoxine or a derivative thereof can be formulated for immediate release upon administration to a subject. In certain of the above-described methods of the invention, metadoxine or a derivative thereof can be formulated for sustained and/or controlled release, and can optionally be formulated to have both immediate release and sustained and/or controlled release characteristics following administration to a subject. In certain embodiments, metadoxine or a derivative thereof is formulated for long-term administration. The metadoxine or metadoxine derivative formulations used in the present invention are described in more detail below.
Metadoxine or metadoxine derivative formulations and administration regimens
In certain embodiments, the present invention provides a composition comprising metadoxine or a derivative thereof formulated for sustained and/or controlled release for use in improving or treating a cognitive disorder as defined herein when administered to a subject.
In certain embodiments, the present invention provides a composition comprising metadoxine or a derivative thereof, wherein a portion of metadoxine or a derivative is formulated for sustained and/or controlled release and a portion of metadoxine or a derivative is formulated for immediate release, when administered to a subject, for ameliorating or treating a cognitive disorder as defined herein.
In certain embodiments, effective serum levels of the active ingredient are achieved within about 10 to about 20 or 30 or 40 or 50 or 60, 90 minutes, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h after administration of metadoxine or a metadoxine derivative. In certain embodiments, effective serum levels of the active ingredient are achieved in the subject within about 5 to about 20 or 30 or 40 or 50 or 60, 90 minutes, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h after administration of metadoxine or a metadoxine derivative. In certain embodiments, effective serum levels of the active ingredient are achieved in the subject within about 20 to about 20 or 30 or 40 or 50 or 60, 90 minutes, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h after administration of metadoxine or a metadoxine derivative. In certain embodiments, an effective serum level of the active ingredient is achieved in the subject about 5, 10, 15, 20, 30, 40, 50 or 60, 90 minutes, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h after administration of metadoxine or a metadoxine derivative.
The present inventors have developed new methods for administering metadoxine or metadoxine derivatives based on the gastrointestinal (through the digestive tract) and/or parenteral (other routes than the digestive tract) route (WO 2009/004629). These methods provide rational design of delivery systems with desired properties based on careful selection of carriers, e.g., embedding the active agent with a suitable surfactant/co-surfactant composition or micro/nanoparticles (e.g., liposomes or nanoliposomes), or other additives or excipients, for the targeted delivery system.
The enteral delivery system may be designed for oral administration (tablets, sachets (sachets), lozenges, capsules, soft capsules, drops or other palatable forms) or rectal administration (suppositories or (micro) enema forms).
Furthermore, the target delivery system may be in liquid form, e.g. drop solutions, syrups. Furthermore, the target delivery system may be in the form of a beverage or food. Thus, the active ingredients used in the present invention may be included in beverages, especially soft drinks (e.g., juices, nectars, water, sodas and other soda drinks, milkshakes, and other milk-based drinks, etc. the liquid formulation may also be in the form of a concentrated syrup for dilution with water or soda water. alternatively, the active ingredients may be included in foods (e.g., snack bar, health bars, biscuits, cookies, candies, confectionery products, ice creams, ice lollies, etc.).
Furthermore, the delivery system may be a food or beverage comprising a physiologically active pyridoxine derivative, in particular pyridoxine L, 2-pyrrolidone-5 carboxylate (metadoxine). In certain embodiments, ingestion of a food or beverage article of the present invention may result in the serum levels of the active ingredient being reached after about 10 to about 40-60 minutes after its ingestion. Examples are candies, chocolates, candy and candy bars, energy bars, ice cream, pastry products and the like.
Parenteral administration includes subcutaneous, transdermal (diffusion through intact skin), transmucosal (diffusion through mucous membrane), sublingual, buccal (absorption through the gum line near the cheek) administration or administration by inhalation. In certain embodiments, the compositions used in the present invention are not administered by invasive therapeutic means (i.e., are non-invasive). In certain embodiments, the metadoxine or metadoxine derivative composition is not administered by intravenous injection.
In certain embodiments, the compositions used in the present invention are delivered as a microcrystalline powder or a solution suitable for aerosolization; for intravaginal or intrarectal administration, pessaries, suppositories, creams or foams. Preferably the formulation is a formulation for oral administration. Another preferred formulation is one for topical application. Another preferred formulation is for transmucosal administration, sublingual, buccal (through the gum line absorption near the cheek), administration by inhalation, or ocular (e.g., as eye drops).
The administration of metadoxine or metadoxine derivatives for medical use requires a safe and efficient delivery system. Due to their particular physicochemical properties, in particular direct absorption by non-invasive means and thus avoiding side reactions, the present invention provides a delivery system for the safe delivery of a wide variety of substances. Based on its unique physicochemical properties, the delivery system significantly enhances the absorption efficiency and quality of metadoxine or metadoxine derivatives, which enables the delivery of lower concentrations or amounts of active substances to a subject in a biologically active form. The delivery system of the present invention provides immediate or near immediate access of the active substance to the tissue and thus provides immediate or near immediate action of metadoxine or metadoxine derivatives to the subject being treated.
Thus, in certain embodiments, the present invention uses a non-invasive drug delivery system for improved administration of a physiologically active pyridoxine, in particular pyridoxine L, 2-pyrrolidone-5 carboxylate (metadoxine), or a physiologically acceptable derivative thereof, comprising said physiologically active pyridoxine as an active ingredient in a suitable carrier. In certain embodiments, serum levels of the active ingredient are achieved within about 10 to about 40-60 minutes after administration.
In another embodiment, the present invention uses a non-invasive drug delivery system for improved administration of physiologically active pyridoxine derivatives, in particular pyridoxine L, 2-pyrrolidone-5 carboxylate (metadoxine), for improving cognitive performance in a subject in need thereof, comprising said pyridoxine derivatives as active ingredient in a suitable carrier. In certain embodiments, the serum level of the active ingredient is achieved within about 10 to about 40-60 minutes after administration.
In certain embodiments, the drug delivery systems used in the present invention may be designed for oral, nasal, ocular, rectal, subcutaneous, transdermal, transmucosal, sublingual, buccal or inhalation administration. The drug delivery system may provide the active substance in a controlled release manner. In certain embodiments, the drug delivery system of the present invention may further comprise at least one additional pharmaceutically active agent.
The delivery system used in the present invention may generally comprise a buffer (a substance that regulates its osmotic pressure), and optionally one or more pharmaceutically acceptable carriers, excipients and/or additives known in the art. Supplementary pharmaceutically acceptable active ingredients may also be incorporated into the composition. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Suitable fluidity can be maintained, for example, by the use of a coating (e.g., lecithin), by the maintenance of the required particle size in the dispersion and by the use of surfactants.
As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, and the like. Such media and agents for pharmaceutically active substances are well known in the art.
Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. It is contemplated that the active agent is delivered by any pharmaceutically acceptable route and in any pharmaceutically acceptable dosage form.
Oral forms include, but are not limited to, tablets, capsules, pills, sachets, lozenges, drops, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Also included are oral fast release, time controlled release and delayed release pharmaceutical dosage forms. The active pharmaceutical ingredients may be administered in a single dosage form or together or separately in different dosage forms. The active pharmaceutical ingredient may be administered in admixture with: suitable pharmaceutically acceptable diluents, excipients or carriers (collectively referred to herein as "carriers"), materials suitably selected for the intended form of administration.
Where the delivery system is for oral administration and is in the form of a tablet or capsule or the like, the active pharmaceutical ingredient may be combined with a non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methylcellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and other reduced and non-reduced sugars, magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like. For oral administration in liquid form, the active pharmaceutical ingredient may be combined with a non-toxic pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water and the like. Suitable binders, lubricants, disintegrating agents, and coloring and flavoring agents can also be incorporated into the mixture, as needed or desired. Stabilizers such as antioxidants, propyl gallate, sodium ascorbate, citric acid, calcium metabisulfite, hydroquinone, and 7-hydroxycoumarin may also be added to stabilize the dosage form. Other suitable compounds may include gels, sweeteners, natural and synthetic gums (gum) (e.g., gum arabic, tragacanth) or alginates, carboxymethylcellulose, polyethylene, glycols, waxes, and the like.
Other suitable pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, ammonia, aluminum stearate, magnesium stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glycerols of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyploid propylene block polymers, polyethylene glycol, and wool fat. In some embodiments, the pharmaceutically acceptable carrier is magnesium stearate. Other pharmaceutically acceptable excipients commonly accepted and used are found, for example, in Remington's Pharmaceutical Sciences (Gennaro, a., ed., Mack pub., 1990).
For the purpose of parenteral administration, solutions in suitable oils (e.g., sesame or peanut oil) or aqueous solutions of polypropylene glycol, as well as sterile aqueous solutions of the corresponding water-soluble salts, may be employed. Such aqueous solutions may be suitably buffered if necessary, with sufficient saline or glucose to first render the liquid diluent isotonic. These aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this regard, the sterile aqueous medium employed may be obtained by standard techniques well known to those skilled in the art. Methods of preparing various pharmaceutical compositions with certain amounts of active ingredients are known to those skilled in the art or will be apparent in light of this disclosure.
The half-life of metadoxine in human serum is very short. Lu Yuan et al (chinese. med. j.2007120(2) 160-. A method of prolonging the serum level of the active moiety is to administer the substance in a sustained release formulation. Because metadoxine is readily soluble in water and various biological fluids, it is difficult to maintain its release and extend its absorption time. Thus, achieving sustained release is surprising. Controlled release dosage forms of metadoxine or metadoxine derivatives can be based on a predetermined gradual release of the active ingredient in the biological fluid, resulting in a long lasting effect with little fluctuation in plasma levels.
In certain embodiments, the delivery systems used in the present invention may be administered in a controlled release formulation. In certain embodiments, the attending physician or other skilled artisan will determine the method of administration after assessing the condition and requirements of the subject. One embodiment of the methods of the invention is the administration of a therapeutic compound described herein in a sustained release form. With the compositions and methods of the present invention, any controlled or sustained release method known to one of ordinary skill in the art can be used, for example, Langer, Science 249 (4976): 1527-33 (1990). The methods comprise administering a sustained release composition, suppository, or coated implantable medical device, thereby continuously delivering a therapeutically effective amount of a composition of the invention to the subject of the method. Sustained release may also be achieved using a patch (patch) designed and formulated for this purpose. The compositions of the present invention may be delivered by a capsule that allows for sustained release of the agent over a period of time. Controlled or sustained release compositions include formulations in the form of lipophilic depot medicaments (depots) (e.g., fatty acids, waxes, oils). Also contemplated by the present invention are particulate compositions (e.g., poloxamers or poloxamines) coated with a polymer. The sustained release formulation or device or any topical formulation may also contain a composition that stabilizes the composition or penetrates a physiological barrier (e.g., skin or mask). Exemplary additional components may include any physiologically acceptable detergent or solvent (e.g., dimethyl sulfoxide (DMSO)).
In all embodiments of the present invention, the methods and uses of the present invention may employ compositions comprising the salt adducts defined herein formulated in a single dose. The single dose formulation may be an immediate release formulation, a burst release formulation, an extended release formulation, a sustained release formulation, or other controlled release formulations known to those skilled in the art.
In further embodiments of the methods and uses of the present invention, the composition comprising the salt adduct defined herein may be a combined dosage form formulation, wherein the different types of formulations, i.e. any combination of immediate release, burst release, extended release, sustained release or other controlled release formulations known to the skilled person, are administered to a subject, either in a single dose or separately, simultaneously or sequentially in separate doses, wherein the time interval between administration of the separate doses is determined according to the condition and severity of the disease or disorder in the subject or the physical condition of said subject.
In some embodiments, the compositions used in the methods of the present invention are formulated as a combination dosage form, wherein at least one dosage form of the salt adduct as defined herein is an immediate release form and at least one dosage form of the salt adduct as defined herein (the same or different from the salt adduct formulated in an immediate release formulation) is formulated as a controlled release (slow and/or sustained release) formulation. In other embodiments, the weight ratio of the salt adduct as defined herein comprised in the at least one immediate release formulation and the at least one controlled release formulation may be 1: 1, 1: 2, 2: 1, 3: 2, 2: 3, 1: 3, 3: 1, 4: 1, 1: 4, 5: 2, 2: 5, 1: 5, 5: 1. When such a combination dosage form is used in the method or use of the present invention, the at least one immediate release form and the at least one controlled release form of the salt adduct as defined above may be administered separately, concomitantly, sequentially, simultaneously, sequentially, etc. In some embodiments, the at least one immediate release form is administered first. In other embodiments, the at least one controlled release formulation is administered first.
In certain embodiments, the metadoxine or metadoxine derivative in the compositions of the invention can be formulated for sustained or controlled release over a period of at least 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours. In certain embodiments, the metadoxine or metadoxine derivative in the compositions used in the invention can be formulated for sustained or controlled release over a period of 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours. In certain embodiments, the metadoxine or metadoxine derivative in the compositions used in the present invention can be formulated for sustained or controlled release over a period of time between about 0.5 or 1 or 2 or 3 or 4 hours to about 5, 6, 7, 8, 9, 10, 11 or 1 hour. In certain embodiments, the metadoxine or metadoxine derivative in the compositions used in the present invention can be formulated for sustained or controlled release over a period of between about 5 or 6 or 7 or 8 hours to about 9, 10, 11 or 12 hours.
In certain embodiments, the metadoxine or metadoxine derivative in the compositions used in the present invention may be in an immediate, rapid burst release form.
In certain embodiments, the metadoxine or metadoxine derivative in the compositions used in the invention can be formulated to release up to 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99, 99.5, or 100% of the total metadoxine or metadoxine derivative within about 0.5, 1, 2, 3, 4, 5, 6, 7, or 8 hours. In certain embodiments, the metadoxine or metadoxine derivative in the compositions used in the invention can be formulated to release not less than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 99, 99.5, or 100% of the total metadoxine or metadoxine derivative in about 0.5, 1, 2, 3, 4, 5, 6, 7, or 8 hours.
In certain embodiments, the metadoxine or metadoxine derivative in the compositions used in the present invention may be a combination of sustained or slow release and immediate or fast release dosage forms. In certain embodiments, the ratio of sustained or slow release metadoxine or metadoxine derivative to immediate or fast release metadoxine or metadoxine derivative is, for example, 1 to 99, 5 to 95, 10 to 90, 15 to 85, 20 to 80, 25 to 75, 30 to 70, 35 to 65, 40 to 60, 45 to 55, 50 to 50, 55 to 45, 60 to 40, 65 to 35, 70 to 30, 75 to 25, 80 to 20, 85 to 15, 90 to 10, 95 to 5, or 99 to 1.
In certain embodiments, the polymeric material is used to maintain or control the release of metadoxine or metadoxine derivatives. In certain embodiments, the type and amount of polymeric material used strongly affects the rate of release of metadoxine or metadoxine derivatives from the products of the invention. Examples of polymers include hydrophobic and hydrophilic polymers. Examples of hydrophobic polymers include, but are not limited to, ethylcellulose and other cellulose derivatives, fats (e.g., palm-stearin-stearate), beeswax, sugar wax (glycomax), castor wax (castowax), carnauba wax, glyceryl monostearate or stearyl alcohol), hydrophobic polyacrylic acid derivatives, and hydrophobic methacrylic acid derivatives, and mixtures of these polymers. Hydrophilic polymers include, but are not limited to, hydrophilic cellulose derivatives (e.g., methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, and hydroxyethylmethylcellulose), polyvinyl alcohol, polyethylene, polypropylene, polystyrene, polypropylene, ethylene vinyl acetate copolymer, polypropylene, polyurethane, polyvinylpyrrolidone, polymethyl methacrylate, polyvinyl acetate, polyhydroxyethyl methacrylate, and mixtures of these polymers. Furthermore, any mixture of one or more hydrophobic polymers and one or more hydrophilic polymers may optionally be used.
In certain embodiments, the composition of the invention or the polymeric material used in the composition used in the invention is microcrystalline cellulose, such as "Avicel PH 101" manufactured by FMC BioPolymer's.
In certain embodiments, the composition of the invention or the polymeric material used in the composition used in the invention is hydroxypropyl methylcellulose, such as "methose" manufactured by Shin-Etsu Chemical Co.
In certain embodiments, The polymeric material used in The compositions of or used in The compositions of The present invention is ethyl cellulose, such as "Ethocel" manufactured by The Dow Chemical CompanyTM”。
In certain embodiments, the composition of the invention or the polymeric material used in the composition used in the invention is an acrylic polymer, such as "Eudragit RS" manufactured by Rohm GmbHTM”。
In certain embodiments, the polymeric material used in the compositions of or used in the present invention is colloidal silica, such as "Aerosil" manufactured by DegussaTM”。
In certain embodiments, the polymeric material used in the compositions of or used in the present invention is poly (vinyl acetate), such as "Kollicoat SR" by BASF.
In certain embodiments, the polymeric material used in the composition of the invention or used in the composition of the invention is a solution of ethyl acetate and vinyl acetate, such as "Duro-Tak" manufactured by delascologiclab & Supply, Inc.
In certain embodiments, the compositions of the present invention or compositions for use in the present invention comprise or consist essentially of formula 1. Formula 1 comprises or consists essentially of 100-3000mg metadoxine or metadoxine derivative and 5-20,000mg methose.
In certain embodiments, the compositions of the present invention or compositions for use in the present invention comprise or consist essentially of formula 2. Formula 2 comprises 100-3000mg metadoxine or metadoxine derivatives and 5-7000mg Ethocel E10TMOr consist essentially of, it.
In certain embodiments, the compositions of the present invention or compositions for use in the present invention comprise or consist essentially of formula 3. Formula 3 comprises 100-3000mg metadoxine or metadoxine derivative and 5-20,000mg Eudragit RSTMOr consist essentially of, it.
In certain embodiments, a composition of the invention or a composition for use according to the invention comprises or consists essentially of from about 250, 300, 400, 500, 600, 700, 800 or 900mg to about 1000, 1500, 2000, 2500 or 3000mg metadoxine or metadoxine derivative. In certain embodiments, a composition of or for use in the present invention comprises from about 5, 100, 500, or 1000mg to about 2000, 4000, 10,000, 15,000, or 20,000mg Avicel PH 101TMOr consist essentially of, it. In certain embodiments, a composition of the invention or a composition for use in the invention comprises or consists essentially of from about 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, or 600mg to about 650, 700, 750, 800, 850, 900, 950, 1000, 5000, 10,000, 15,000, or 20,000mg of polymeric material. In certain embodiments, the polymeric material is methose, Ethocel E10TMOr Eudragit RSTM. In certain embodiments, methose comprises or consists essentially of 1 to 90% (preferably 5 to 70%) of the formulation. In certain embodiments, EthocelTMComprises or consists essentially of 1 to 30% (preferably 2 to 20%) of the formulation. In certain embodiments, the EudragitTMComprises or consists essentially of from 1 to 90% (preferably from 5 to 70%) of the formulation.
In certain embodiments, the delivery system of the invention or the delivery system used in the invention comprises a delivery device. In certain embodiments, the composition of the invention or the composition for use in the invention is delivered at a controlled rate by an osmotic process, for example by an osmotic pump. The system may be constructed by coating the osmotically active agent at a rate that controls the semi-permeable membrane. The membrane may contain pores of critical size through which the agent is delivered. Upon contact of the dosage form with an aqueous fluid, the fluid penetration through the membrane and the osmotic pressure of the core formulation absorb water at a predetermined rate. This osmotic imbibition results in the formation of a saturated solution of the active substance in the core, which is released at a controlled rate from the delivery pores of the membrane.
In certain embodiments, biodegradable particles are used to deliver the compositions of the invention or compositions for use in the invention. In certain embodiments, the system for preparing microparticles consists of an organic phase comprising a volatile solvent in which a polymer is dissolved, emulsified in an aqueous phase, and the material to be encapsulated. In certain embodiments, biodegradable polymers useful in the microparticle matrix include polylactic acid (PLA) or copolymers of lactic acid and glycolic acid (PLAGA). The PLAGA polymer degrades hydrolytically over time into its monomeric components, which are easily removed from the body by natural metabolism.
The formulation of the invention or the formulation for use in the invention may further comprise an absorption enhancer and other optional components. Examples of absorption enhancers include, but are not limited to, cyclodextrins, phospholipids, chitosan, DMSO, tween, Brij, glycocholate, saponin, fusidate, and energy-based absorption-enhancing devices.
Optional components present in the dosage form include, but are not limited to, diluents, binders, lubricants, surfactants, colorants, flavoring agents, buffers, preservatives, stabilizers, and the like.
Diluents, also known as "fillers," include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, hydrated starch, silicon dioxide, silica gel, titanium oxide, aluminum oxide, talc, microcrystalline cellulose, and powdered sugar, for example. For administration in liquid form, diluents include, for example, ethanol, sorbitol, glycerol, water, and the like.
An adhesive is used to impart adhesive properties to the formulation. Suitable binder materials include, but are not limited to, starches (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose, lactose, and sorbitol), polyethylene glycols, waxes, natural and synthetic gums (e.g., gum arabic, tragacanth, sodium alginate, cellulose, and Veegum), and synthetic polymers (e.g., polymethacrylates and polyvinylpyrrolidone).
Lubricants are used to assist in production; examples of suitable lubricants include, for example, magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol.
The surfactant may be an anionic, cationic, amphiphilic or nonionic surfactant, preferably an anionic surfactant. Suitable surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions in combination with cations (sodium, potassium, and ammonium ions). Particularly preferred surfactants include, but are not limited to, long alkyl chain sulfonates and alkylaryl sulfonates (e.g., sodium dodecylbenzene sulfonate); sodium dialkyl sulfosuccinates (e.g., sodium bis- (2-ethylhexyl) -sulfosuccinate); and alkyl sulfates (e.g., sodium lauryl sulfate).
Stabilizers (e.g., antioxidants) include, but are not limited to, propyl gallate, sodium ascorbate, citric acid, calcium metabisulfite, hydroquinone, and 7-hydroxycoumarin.
The compositions of the invention or the compositions for use in the invention may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives and the like, if desired.
Any of the compositions of the invention or compositions for use in the invention may be used alone or in combination with one or more other therapeutic agents to improve cognitive performance. Examples of other therapeutic agents are: amphetamine, methylphenidate hydrochloride, dexmethylphenidate hydrochloride, atomoxetine, reboxetine, fluoxetine, sertraline, paroxetine, fluoxamine, citalopram, venlafaxine, bupropion, nefazodone and mirtazapine.
The amount of both the compound and the additional therapeutic agent that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the composition of the invention should be formulated such that a dose of between 0.1 and 1g/kg body weight/day, preferably 0.1 to 300mg/kg body weight, can be administered. The dosage of the compound depends on the condition and disease of the patient, as well as the daily dosage required. In human therapy, the daily oral dose is preferably 10-3000 mg. These doses are administered in unit dosage form, and in some cases may be divided into 2-3 smaller doses for each day (especially in oral therapy).
In certain embodiments, the compositions of the present invention may act synergistically in combination with each other, as well as in the presence of other therapeutic agents. Thus, the amount of compound and other therapeutic agent in such compositions is lower than that required for monotherapy using only the therapeutic agent. In this composition, 0.1-1g/kg body weight/day of other therapeutic agent may be administered.
Use of metadoxine or metadoxine derivatives for preparing therapeutic compositions
In certain embodiments, the present invention provides the use of metadoxine or a metadoxine derivative (including functional, physiologically acceptable metadoxine derivatives) in the manufacture of a therapeutic composition for administration to a subject for improving cognitive function or treating and/or preventing a cognitive disorder or a cognitive dysfunction according to any of the methods of the invention described herein.
Examples
The following examples are intended to illustrate the invention. The examples are not limiting and the skilled person will realize that other embodiments are within the scope of the invention. Unless otherwise stated, the procedure is carried out using techniques understood by those of ordinary skill in the art.
Example 1 Metadoxine Release from various formulations
Metadoxine was formulated according to table 1 in various immediate and slow release ratios:
table 1: metadoxine formulations
The above formulation was administered to fasted healthy patients. Blood samples were collected on a predetermined schedule to characterize absorption and clearance of the formulation. The results are shown in FIG. 1.
Figure 1 shows that metadoxine reaches its maximum concentration after about 0.5 hours and can remain in the blood for up to about 7 hours. In healthy caucasian subjects, C is shown in a dose range of 700 to 2100mgmaxAnd AUC dose linearity.
Table 2: mean pharmacokinetic parameters after single dose administration of 700mg, 1400mg and 2100mg metadoxine to healthy caucasian adults
Example 2 Metadoxine formulation for improving cognitive Performance in ADHD/ADD patients
38 ADHD/ADD adult patients (ages 18-45) were tested for the Geha Mental Health Center (Israel) ADHD disease area.
A total of 4 tablets were administered to each patient:
two-tablet Immediate Release (IR) formulation (defined in table 3) and
two-tablet Slow Release (SR) formulations (defined in table 4).
In a dual (immediate and slow phase combination) release formulation, the total dose of metadoxine administered was 1400 mg.
Table 3: parameters of IR drug product batch
Table 4: parameters of SR drug products
The tests at the time of addition (inclusion) included patient selection and included clinical diagnosis with DSM IV, mental examination, WURS & ASRS questionnaire, TOVA (Test of Variablesof Attention) score, Wechsler (Wechsler Adult Intelligent Scale) subtest, BDT (beck suppression inventory) and STAT (STAT-it Tranxiety inventory) questionnaire. More than 1 week after entry, participants were given a single dose of metadoxine SR (1400mg) and re-tested for Wechsler and TOVA after 90 minutes.
TOVA is a computerized test developed to assess attention and impulsivity in the normal and clinical population. The main outcome measures of the TOVA measurement are the Omission criterion score (SS; a measure of inattentiveness), the error criterion score (Commission Standard score) (SS; a measure of impulse control), the Reaction Time (RT) SS, the variability of the RT SS, and the overall ADHD SS (composite score of previous sub-measurements).
The primary outcome measures were ADHD score, TOVA omission, TOVA make mistakes, TOVA RT and TOVA variability (analyzed as% of standard score compared to previous TOVA test performance of patients at baseline). The secondary outcome measure is a subtest by Weschler: numeric range, symbol search, numeric symbol.
As a result:
table 5: results of TOVA
(variable test of attention continuity Performance measurement)
＊And (3) normal: ADHD score > -1.8, omission, error, reaction time and variability score: 85-115
The results of the TOVA test showed statistically significant improvement in all those parameters associated with inattention (number of misses, greater stability with reaction time and reduction in overall ADHD score) and those associated with impulsion (number of mistakes).
Table 6: results of the Wechsler subtest
The results of the Wechsler subtest demonstrate the ability of metadoxine to improve cognitive function in an ADHD adult population.
Discussion:
comparing the overall ADHD score results obtained with the metadoxine SR formulation of the invention to the baseline score (see table 7 below), shows an improvement of the ADHD standard score of about + 90% over baseline.
Table 7: comparison of ADHD scores
(patients treated with metadoxine)
＊The average difference at the 0.05 level was significant
1Adjustments were used for multiple comparisons: bonferroni
Example 3 Metadoxine formulation for improving cognitive Performance in ADHD/ADD patients
10 ADHD/ADHD adult patients (ages 18-45) were tested for the Geha Mental Health Center (Israel) ADHD lesion.
A single tablet containing a 1400mg dose of DER metadoxine was administered to each patient.
Metadoxine was administered in a dual extended release dosage form at a total dose of 1400 mg.
The tests at the time of entry included patient selection and included clinical diagnosis on DSM IV, mental examination, WURS & ASRS questionnaire, TOVA (Attention Change Test, Test of Variables of Attention) score, Wechsler (Wechsler Adult Intelligent Scale), BDI (BeckDepression Inventory) and STAI (State-score analysis Inventory) questionnaire.
After entry, participants were given a single dose of metadoxine DER (1400mg) and subjected to the TOVA test after the following time period: 90 minutes, 4 hours and 7 hours.
TOVA is a computerized test developed to assess attention and impulsivity in the normal and clinical population. The main results of the TOVA measurements are missing criteria score (SS; inattentive measurement), error criteria score (SS; impulse control measurement), Reaction Time (RT) SS, variability of RTSS, and overall ADHD SS (composite score of previous sub-measurements).
The primary outcome measures ADHD score, TOVA omission, TOVA error, TOVART, and TOVA variability (analyzed as standard scores expressed as% of performance compared to the baseline of the patient's previous TOVA test). Secondary outcome measures sub-tests of Weschler: numeric range, symbol search, numeric symbol.
Results and discussion:
as shown in table 8, ADHD score, RT time, and RT variability (which are considered to be more sensitive parameters in the adult population) showed significant improvement at all time points after baseline, with the maximum results shown at 4 hours. It was noted that even 90 minutes after dosing, the wrong results showed an improvement. It was also noted that 7 hours after the administration, the improvement effect became small, but the improved results were shown relative to the baseline.
TABLE 8
Example 4 Effect of Metadoxine on cognitive Performance in sleep deprived subjects
After 24 hours of complete sleep deprivation (TSD), double blind studies compared cognitive performance of 14 healthy adults (ages 18-40) using cognitive tasks.
Standardized neuropsychological tests are performed in cognitive domains (e.g., speed of processing, attention, and inhibition) previously demonstrated to be affected by sleep and/or sleep deprivation.
All participants worn activity change recorders (actigraph) to record sleep-wake behavior before and during the study.
Each participant was given one of two treatment conditions in balance: (1) the composition of the invention (single dose 1400mg DER metadoxine) or (2) placebo.
Method of producing a composite material
a. The sleep scheme comprises the following steps:
on the day of study, participants were instructed to:
1. get up no later than 08:00 (at home).
2. Doze off throughout the day and abstain from using any alcohol or stimulant.
3. The sleep laboratory was reached at 20: 00.
4. Stay awake (supervised) overnight.
5. From 05:00, abstain from ingesting any food or liquid.
6. The next 07:00 days, participants received the composition of the invention or placebo from a physician or licensed nurse participating in the study.
At 7.08:30, the participants performed cognitive tasks (task duration: 30 minutes).
b.Activity change recorder. The actigraph is a small, lightweight device (the size of a wristwatch) placed on the subject's non-dominant wrist with a motion sensor (accelerometer) that collects body motion data (sampled multiple times per second and stored at a 1 minute time period (epoch)). Sleep/awake patterns were monitored using a change of activity recorder that has been validated against multifunctional sleep recording (polysomnography), resulting in high correlation for sleep measurements. From 1 week before the start of the experimental phase, the participants continued wearing the activity change recorder until the end of the activity program. The activity change recorder is waterproof and durable and is worn using a non-removable wristband for a guaranteed period of continuous wear.
c neuropsychological testing.
The Digital Symbol Substitution Test (DSST) (WAIS-III) is a task of pen-paper processing speed, which measures visual motion coordination and processing speed. Which consists of 9 pairs of digit-symbols followed by a column of digits. The object is required to write the corresponding symbol as quickly as possible under each number. The number of correct symbols within the allowed time (120 seconds) is measured.
The Connors' continuous performance task (CPT; www.bdikatkeshev.co.il, Tel-aviv university) is a computerized task that covers the cognitive domain reported to be affected by sleep or sleep deficits, including processing speed, attention, and suppression. Different figures are flashed in sequence on the computer screen and the participant is instructed to react as quickly as possible to some figures (using the keyboard) and suppress other figures (i.e. not react). This task took about 17 minutes to complete.
The numerical range (WAIS-III) is a test of attention, concentration and working memory. The subject is repeated with the sets of numbers starting forward and then going backward. This task takes about 5 minutes to complete.
The rhythmic Auditory Serial Addition Task 3 rd edition (PASAT-III) is a computerized Task that measures Auditory information processing speed and flexibility, as well as working memory. A single number is presented every 3 seconds (trial 1) or every 2 seconds (trial 2), and the patient must add each new number to the number immediately preceding that number. PASAT is presented in the CD to control the speed of stimulus presentation. The test score is the total number (among 60 possibilities) that gives the correct number in each trial. This task takes about 8 minutes to complete.
The test was performed by trained personnel, which took 45 minutes to complete.
At the end of each cognitive testing session, a Karolinska wakefulness Scale (KSS: 9 point Scale) was performed along with a series of 10 point Likert scales asking for good performance of the sport, ability to concentrate on attention, effort required to complete the task and perceived task difficulty. The problem of Likert is to detect whether performance is associated with subjective effort, task difficulty, or insomnia.
Results and discussion
The results show a clear trend in the efficacy of DER metadoxine treatment versus placebo treatment. Table 8 shows the significance of the difference (Δ) between placebo and drug results:
TABLE 8
Example 5 Metadoxine formulations for improving cognitive function in elderly subjects
At the beginning of the study (control 1), after 1 week of twice daily administration of 350mg metadoxine formulation (test 1), after 1 week of washout period (control 2) and after 1 week of administration of placebo formulation (test 2), 25 patients 60-79 years old with Mild Cognitive Impairment (MCI) were subjected to computerized neuropsychological tests (Mindstreams).
The results were analyzed for differences between the control and the test. The use of the drug is expected to improve some parameters compared to placebo, for example: digital memory and pattern memory.
Example 6 Metadoxine formulations for improving cognitive Performance in fatigue Subjects
After 30 hours without any sleep, 20 physicians performed Ray's memory test (Ray' memory test) at the beginning of the study (control) (baseline of the study) and 1 hour after administration of metadoxine formulation (test).
The results were analyzed for differences between the control and the test. It is expected that in the treated group, the use of the drug improves some parameters compared to the control, for example: the number of words is remembered.
Example 7 Metadoxine formulations for improving cognitive Performance in Alzheimer's Disease (AD) patients
Memory testing was performed on 20 AD patients at the beginning of the study-control (baseline of the study) and 1 month after administration of metadoxine formulation.
The results were analyzed for differences between the control and the test. Some parameters are expected to improve after dosing compared to controls, for example: and (4) digital recall.
Example 8-Metadoxine formulation for improving cognitive performance in Multiple Sclerosis (MS) patients.
Memory testing was performed on 20 MS patients at the beginning of the study-the control (baseline of the study) and 1 month after administration of the metadoxine formulation.
The results were analyzed for differences between the control and the test. Some parameters are expected to improve after dosing compared to controls, for example: and (4) digital recall.
Example 9 treatment of SWSD (Shift Work Sleep disorder) Disporder) metadoxine formulations
60 volunteers with chronic SWSD were divided into 2 groups: one group of volunteers received metadoxine 700mg SR capsules, while the other group of volunteers received placebo capsules. Both groups were tested: psychomotor Vigilance Task (10 minute visual constant attention test, which is sensitive to sleep), continuous performance test (CPT-14 minute computer alert Task) and simulated driving Task (20 minute driving Task, which is sensitive to sleep, running in a computer equipped with software, steering wheel, throttle and brake). Testing was performed at baseline and after treatment.
The results of the measured parameters were analyzed: reaction time, mistakes, omissions, trajectory variability and speed variability. The results are expected to be better for the metadoxine-receiving group.
Example 10-comparative dissolution test: immediate release versus slow release
The immediate release tablets were prepared using a high shear wet granulation technique according to the following composition:
slow release tablets were prepared using a high shear wet granulation technique according to the following composition:
dissolution was tested in 500ml of small intestinal fluid at pH 6.8 using USP apparatus 2 (paddle), (50 × rpm) at 37 ℃. The results of comparative dissolution are shown in figure 2. Over 0.5 hours, the immediate release formulation released over 90%, while over 8 hours, the slow release tablet released about 70%.
Example 11 Slow Release capsules of Metadoxine
Granulation was performed using high shear granulation and vacuum drying. The following acrylic hydrophobic polymers are exemplified as the polymeric material.
Metadoxin 350 mg/capsule
Calcium carbonate 45 mg/capsule
Eudragit RSTM60 mg/capsule
The materials were mixed together and Eudragit RS usedTMGranulating with ethanol solution. Encapsulating the granules in gel capsules.
Example 12 controlled Release syrup of Metadoxine
Syrups were prepared using an overhead rotary mixer (overhead rotary mixer).
Metadoxine granule 700 mg/5 ml
Cherry flavor seasoning 10 mg/5 ml
Xylitol solution was added to a volume of 5 ml
Slow release granules of metadoxine (from example 8) were mixed in a xylitol solution. Adding cherry flavoring agent.
Example 13 Metadoxine easy-to-swallow sachets (Ready-to-swallow sachets)
Two granulations were performed in a mixing granulator:
particle No. 1:
metadoxine 500mg
PVP K-2510 mg
Particle No. 2:
metadoxine 800 mg
Metholose 90SH 200 mg
Ethocel E10TM50mg of
And (3) final mixing:
magnesium stearate 10 mg
Aerosil 200TM5 mg of
Strawberry flavor seasoning 10 mg
Granule No 1 (immediate absorption formulation) and granule No 2 (slow release formulation) were mixed together with the other ingredients and filled into sachets.
Example 14 skin Patch of Metadoxine (patch)
The materials (below) were mixed together to form a clear gel. The gel is coated onto the carrier film by using a coating apparatus. The laminate was dried and a polyester release liner (release liner) was superimposed on the dried metadoxine gel. The sheet was cut into patches and stored in a cool place.
Example 15 Metadoxine effervescent powder
Preparation of microparticles (granules) using extrusion technique:
100mg of metadoxine
Metholose 90SH 35 mg
Mixing the granules with the following ingredients
The compound was filled into sachets.

Claims (16)

1. Use of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5-to 7-membered lactam ring, optionally additionally substituted, for the preparation of a medicament for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition in a subject.
2. Use of a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5-to 7-membered lactam ring, optionally additionally substituted, for the preparation of a medicament for improving cognitive function in a healthy subject.
3. Use according to claim 1 or 2, wherein the positively charged moiety is a compound of formula (I):
wherein
R1Is straight or branched C1-C6An alkyl group;
R2selected from-OH, straight or branched C1-C6Alkoxy and straight or branched C1-C6An alkoxycarbonyl group;
R3and R4Each independently selected from: formyl, optionally with at least one halogen, amine, hydroxy, C1-C6Alkoxy, mercapto and C1-C6Alkoxycarbonyl-substituted straight or branched C1-C6An alkyl group.
4. Use according to any one of the preceding claims, wherein the carboxylated lactam ring is selected from the group consisting of:
wherein
R6Selected from: H. straight or branched chain C optionally substituted with at least one halogen1-C6Alkyl, straight or branched C2-C6Alkenyl, straight-chain or branched C2-C6Alkynyl, cycloalkyl, aryl and heteroaryl, optionally with C1-C6Alkyl substitution;
R7、R8、R9、R10、R11、R12、R13and R14Each independently selected from: H. straight or branched C1-C6Alkyl radical, C2-C6Alkenyl radical, C2-C6Alkynyl, cycloalkyl, aryl and heteroaryl, optionally substituted with at least one group selected from: c1-C6Alkyl, halogen, amino, cyano, nitro, mercapto, C1-C6Alkoxy, aminocarbonyl, C1-C6Alkoxycarbonyl group, C1-C6Carboxyalkyl, C1-C6Alkoxycarbonylalkyl and amidino.
5. Use according to any one of the preceding claims, wherein the salt adduct is selected from the following:
6. the use according to claim 1, wherein the cognitive disease, disorder or condition is selected from the group consisting of: attention deficit/hyperactivity disorder (ADHD/ADD), memory disorder (amnesia), arousal disorder, mental fatigue disorder, shift work sleep disorder, narcolepsy, obstructive sleep apnea/hypopnea syndrome, poor concentration and concentration, or any combination thereof.
7. The use according to claim 1, wherein the cognitive disease, disorder or condition is selected from the group consisting of: learning disability, memory impairment, cognitive dysfunction, cognitive function alterations including alzheimer's disease, or any type of encephalopathy including uremic encephalopathy and hepatic encephalopathy.
8. The use according to claim 1, wherein the cognitive disease, disorder or condition is a neurobehavioral disease, disorder or condition.
9. The use according to claim 8, wherein the neurobehavioral disease, disorder or condition is selected from: attention Deficit Hyperactivity Disorder (ADHD), Attention Deficit Disorder (ADD), memory disorders, poor concentration, and poor concentration.
10. The use according to claim 1, wherein the cognitive disease, disorder or condition is selected from the group consisting of: attention Deficit Disorder (ADD) or hyperactivity disorder (ADHD/ADD), memory disorder (amnesia), arousal disorder, mental fatigue disorder, shift work sleep disorder, narcolepsy, obstructive sleep apnea/hypopnea syndrome, poor concentration and concentration, or any combination thereof.
11. Use according to claim 2, wherein the cognitive function is selected from: temporary or long term no learning ability, temporary or long term memory impairment, temporary or long term cognitive dysfunction, temporary or long term cognitive function change, temporary or long term attention concentration impairment, temporary or long term attention convergence impairment, temporary or long term arousal impairment, temporary or long term mental fatigue disorder, temporary or long term shift work sleep impairment, or any combination thereof.
12. Use according to any one of the preceding claims, wherein the subject is a child, adolescent, adult or elderly.
13. Use according to any one of the preceding claims, wherein the salt adduct is formulated as a sustained, delayed or controlled release dosage form.
14. Use according to any one of the preceding claims, wherein the salt adduct is formulated as a sustained, delayed or controlled release dosage form in combination with a salt adduct formulated as an immediate or burst acting dosage form.
15. Use according to any one of the preceding claims, wherein the salt adduct is formulated to deliver up to 0.1-1000mg/kg body weight/day of the salt adduct, preferably 1-400mg/kg body weight of the salt adduct in a single dose administration or a portion thereof.
16. Use according to any one of the preceding claims, wherein the salt adduct is formulated with at least one further pharmaceutically active agent.
HK12112125.9A 2009-06-25 2010-06-24 A method for the treatment, alleviation of symptoms of, relieving, improving and preventing a cognitive disease, disorder or condition HK1171370B (en)

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